US4590001A - Platinum bound to transferrin for use in the treatment of breast tumors - Google Patents
Platinum bound to transferrin for use in the treatment of breast tumors Download PDFInfo
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- US4590001A US4590001A US06/593,725 US59372584A US4590001A US 4590001 A US4590001 A US 4590001A US 59372584 A US59372584 A US 59372584A US 4590001 A US4590001 A US 4590001A
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- transferrin
- platinum
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- cells
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/79—Transferrins, e.g. lactoferrins, ovotransferrins
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- Transferrin is a protein found in the blood of all humans and its known function is to carry iron to those organs and cells of the body that require this metal for normal function. Recently, scientists have reported that an important function of iron carried by transferrin is to control the division of body cells. E. Robbins et al. Proceedings National Academy Science U.S.A., 66: 1244 (1970); P. Rudland, et. al., Biochemical Biophysical Research Communications, 75: 556 (1977). It has been known for some time that when a person becomes afflicted with a neoplastic growth, the quantity of iron in the blod carried by transferrin is severely diminished. M. Beamish, et. al., British Journal of Cancer, 26: 444 (1972); N.
- platinum Because of its toxicity, platinum has been used in the past in organometallic moieties and compounds to treat neoplastic growths, for instance in U.S. Pat. Nos. 4,053,587, 4,151,185, 4,169,846, 4,175,133, 4,177,263, 4,206,208, 4,234,499, 4,234,500, 4,284,579.
- these previous therapeutic agents incorporating platinum had severe drawbacks in a clinical context. Specifically, the platinum chemotherapeutic agents would not specifically attack and kill the neoplastic cells, but instead caused damage to normal cells as well. Many of the platinum compounds also activated the body's immune systems, creating further side effects and causing the foreign substances to be rapidly removed from the body, thereby reducing the therapeutic effect of the drugs.
- the specific form of the platinum starting material which has been found most useful in therapeutic applications is cis-Dichlorodiammineplatinum (II).
- the invention is not limited to cis-Dichlorodiammineplatinum (II), since other inorganic platinum starting materials may be useful.
- most research to date in the field of oncology has focused on cis-Dichloradiammineplatinum (II) (cis-platinum)
- a novel treatment for breast cancer has been devised having properties which give it the potential for treating breast cancer.
- the unique characteristics of this new anti-neoplastic chemotherapeutic agent that make it so attractive are (1) its potential capability of specifically killing breast tumor cells while having little or no effect on normal, slower growing cells; (2) it is relatively inexpensive to manufacture, thereby making it more generally available to cancer victims; (3) it is not recognized as a foreign substance by the body's immune system since the platinum is cloaked in a naturally occuring body protein.
- Platinum-transferrin is prepared by reacting at 0°-5° C. cis-platinum dichlorodiammine platinum (II), or other inorganic platinum compounds, with pure, essentially iron-free transferrin in the presence of bicarbonate anion after chemically protecting the sulfhydro groups of the transferrin with an excess of cystine.
- the platinum transferrin is dialyzed to remove the weak organic acid and bicarbonate anion, passed through molecular sieves to separate polymeric platinum-transferrin from the monomeric product, and the monomeric product is thereafter concentrated to a therapeutically useful concentration.
- FIG. 1 shows that the rate of growth of feline lymphoma cells was slowed to approximately one-half that of the controls when treated with platinum-transferrin dissolved in phosphate buffered saline. The doubling time for the treated cells was 7.8 days as compared to 4.4 days for untreated control cells. Even though these feline cells were not killed the results are very important because human transferrin, which was used, is not generally genetically compatible with cat cells.
- platinum-transferrin is shown to kill human HeLa cells (derived from human cervical cancer) within 7 days. It is interesting to note from FIG. 2 that the killing process was initiated immediately upon exposure to platinum-transferrin. (Platinum-transferrin was introduced into the culture medium 24 hours after seeding.)
- the tissue cultures leading to the results shown in FIGS. 1-3 were prepared by obtaining the feline lymphoma cells, human HeLa tissue, and lympho-blastoid cell cultures from the American Type Culture Collection, which is the usual source of such materials.
- the cultures were placed in flasks in Eagle's medium, and the flasks were placed in a computerized incubator of the type that is well known in the art.
- the incubator was maintained at 37° C., with a humidity of about 70%, and the air contained about 5% CO 2 .
- the tissue cultures were then checked every two days and the doublings counted to obtain the data shown in FIGS. 1-3. When a 10% excess of platinum-transferrin dissolved in phosphate buffered saline was pipeted into the culture medium, cell growth began to decrease.
- Patient A was a 38-year-old white female suffering from infiltrating lobular carcinoma who had undergone a total mastectomy and axillary dissection. She was later found to have leptomeningeal metastasis with spinal fluid showing viable tumor cells; there was also evidence of bone involvment. After a conventional course of chemotherapy on Nolvadex and Methotrexate had failed, the patient's condition continued to worsen until she became practically moribund. Therefore, she was started on a course of platinum-transferrin intravenously, and improved dramatically. She was given injections in the following amounts during the indicated weeks, wherein week 1 was the week during which the initial dose was administered:
- Patient B was a 52-year-old white female with far advanced local carcinoma of the left breast who was diagnosed as having a very aggressive infiltrating ductal carcinoma. After traditional chemotherapy with Tamoxifen (Nolvadex) showed little response, she was started on the platinum-transferrin complex and given injections regularly. These injections were given on the following dates in the indicated amounts:
- Patients C and D have also been treated for infiltrating ductal carcinoma with the platinum-transferrin complex. Both these patients have improved as a result of this therapy.
- platinum-transferrin as an anti-neoplastic agent can be put in proper perspective by comparing its properties with those of a theoretically excellent clinical agent for treating malignancies.
- Such an agent should specifically attack and kill rapidly multiplying cancer cells and not damage normal cells.
- the agent should not be destroyed by the body's defense mechanism against foreign substances, because such destruction greatly reduces the length of time the anti-neoplastic agent acts effectively to eradicate cancer cells. Traumatic side effects to non-malignant cells are minimal, and the dose of the agent necessary to effect eradication of the malignant cells should be minimal. In addition, administration of the drug should cause only minor discomfort to the patient.
- platinum-transferrin composition of the present invention achieves many of the objectives of a theoretically excellent clinical treatment for malignancy. Even though platinum-transferrin will kill rapidly growing human HeLa cells (FIG. 2), it apparently has little effect on slower growing normal human cells (FIG. 3). It has also been found in work with tumor bearing rats and human breast tissue samples that iron specifically carried by transferrin accumulated in larger quantities in tissue containing malignant cells than in surrounding normal tissue. F. Warner, R. Stjernholm and I. Cohn, Medical Physics, 5: 100 (1978); M. Dodd and J. Silcock, British Journal of Cancer, 34: 556 (1976).
- platinum-transferrin as an anti-neoplastic agent is its ability to escape detection and destruction by the human body's immune defense mechanisms against unnatural substances. Since the cell killing agent, platinum, is bound to and hidden in a naturally occurring protein, transferrin, which the body recognizes as being normal, the platinum transferrin has not stimulated immune reactions. By not inducing immune reactions, platinum-transferrin remains in the body and provided longer term, anti-neoplastic activity. The anti-cancer agents presently in clinical use are generally destroyed by the body's defense mechanism within a few days after being administered, so the platinum-transferrin represents a significant advance in the treatment of breast carcinoma.
- transferrin with its attached metal is not known to be excreted from the body and should be more specifically directed to rapidly multiplying breast cells, a smaller quantity of platinum, as platinum-transferrin, can be administered to the patient to effect remission. It also appears that the platinum-transferrin can be administered by injection, thereby avoiding the discomforting intravenous drip technique generally used in the treatment of breast cancer patients.
- the therapeutic dosage of platinum-transferrin has generally been found to be a dosage equivalent to 10% of the normal transferrin in the body of a patient to whom the platinum-transferrin is being administered. For example in a 70 kilogram man, it is generally found that there are 12 grams of normal human transferrin. Such a patient will be given 10% of the 12 grams as a useful therapeutic dosage, or 1.2 grams of platinum-transferrin.
- the therapeutic dosage of platinum compounds not bound to transferrin is usually two to three mg per kilogram of body weight, in contrast to the approximately 0.8-3.0 mg of platinum per person necessary with the cis-platinum-transferrin complex.
- the remarkably lower dosage of cis-platinum-transferrin is made possible because of the breast tumor specific activity of platinum-transferrin.
- Immunodiffusion assays have been performed to determine if the subjects receiving the monomeric platinum-transferrin complex were developing antibodies in their blood to platinum bound human transferrin. These tests were performed on an agar plate stained with commassee blue. A schematic drawing of the plate appears immediately below. Blood serum samples were obtained from Patients A, D, and E. These blood serum samples were placed on the agar plate in the following fashion:
- the plate was placed in a humidified 37° C. incubator for development of precipitation.
- the plates were allowed to develop for about one day, after which time precipitates were observed around drops 1 and 4, the rabbit, anti-human transferrin.
- the precipitates indicated that drops 1 and 4 contained antibodies to the platinum bound human transferrin in drop 0.
- the absence of precipitates between drop 0 and drops numbered 2, 3, 5 and 6 indicated that subjects A, D and E had not developed serum antibodies to the platinum human transferrin.
- transferrin has two receptors, which in the normal human body, bind iron ligands to the transferrin for distribution of iron in the human body.
- Transferrin with a molecular weight of about 77,000 is structured as a single polypeptide chain which contains terminal sialic acid groups on two identical heterosaccharide chains, each linked to an asparagine molecule.
- the two metal binding sites can bind a diverse group of bivalent and trivalent metals, but Fe (III) is bound most tightly so that usually it displaces other metals.
- transferrin receptors include Cr (III), Cu (II), Mn (II), Co (II), Cd (II), Zn (II), Ni (II), Sc, V, Ga, Pt, and the elements of the lanthanide series. Biochemistry of Nonheme Iron, Plenum Press (1980) pp. 145-146. Ruthenium is also known to bind to transferrin and is a toxic metal useful in causing regression of breast tumor cells when bound to transferrin. Gallium is another toxic metal that should be therapeutically useful.
- each of the two iron ligands are replaced with platinum thereby producing a platinum atom to transferrin molecule ratio of approximately 2 to 1.
- the ratio of cis-platinum to iron should be approximately 1.8-2.2 atoms of platinum per molecule of transferrin.
- a bottle having a 15 ml capacity with a screw cap is used as a reaction vessel.
- a 450 mg portion of pure human transferrin (essentially Fe-free) which can be obtained from Sigma Chemical Company, P.O. Box 14508, St. Louis, Mo. 63178 as Product No. T-2252, is dissolved in 10 ml 0.01M citric acid.
- To this mixture is added 12 mg cystine di-hydrochloride in 1 ml 0.1N HCl.
- 3 mg cis-dichloro-diammine platinum (II) powder which can be obtained from Sigma Chemical Company, P.O. Box 14508, St. Louis, Mo. 63178, is added, followed by 200 mg of sodium bicarbonate powder.
- the bottle is capped tightly, and left in a refrigerator at +5° C. for 45 minutes to cool the reaction mixture.
- the solution is transferred to a collodium bag concentrator and dialyzed under negative pressure against 100 ml phosphate buffered saline until the platinum bound transferrin solution is reduced to 5 ml (time 3-5 hours). If a white powder appears (excess cystine) it is removed by centrifugation at 10,000 ⁇ G for 5 minutes. A dimeric and monomeric platinum transferrin remain in solution.
- the remaining clear protein solution is then applied on a Sephadex G-200 column for molecular sieving using phosphate buffered saline. A monomeric transferrin containing platinum is recovered between 250 to 300 ml of eluant.
- This portion is concentrated in an Aminco Concentrator until the protein concentration has reached 35-45 mg per ml. After sterilization with a Millex filter the product is kept in a refrigerator at +5° C. until used. This product contains 1.8-2.2 atoms of platinum per molecule of transferrin.
- the platinum-transferrin must be carefully prepared to avoid polymerization of the product since the polymeric form of platinum transferrin has been found to be ineffective in treating breast tumor cells.
- the product of the process described in Example I achieves both of these goals and results in a product that for the first time is dramatically therapeutically useful. Preparation of the product at a reduced temperature (e..g, 0°-5° C.) often avoids polymerization of the product.
- P-4394 is added followed by 400 mg sodium bicarbonate.
- the bicarbonate anion appears to initiate bonding of the platinum to transferrin.
- the vessel is capped and gently swirled in the ice water until the cis-platinum powder is completely dissolved.
- the screw cap is removed and the solution is placed in a dialysis tubing with MW cutoff of 12,000 obtained from Scientific Products and dialyzed against 500 ml phosphate buffered saline for 12 hrs. to remove the citrate and bicarbonate ions.
- the dialyzate is discarded and the content of the dialysis tubing is then applied on a K-25/100 cm column (Pharmacia) packed with a slurry of Sephadex G-200 (Pharmacia) for molecular sieving.
- the platinum-transferrin is eluted with phosphate buffered saline.
- a dimeric form of the platinum transferrin is eluted between 180-230 ml.
- the dimeric form is discarded because it is an artifact of procedure.
- the monomeric form of platinum-transferrin is eluted from the column between 250-330 ml.
- This solution is concentrated to 10 ml (which is about 50 mg/ml) using an Aminco concentrator, Model 52 (Amicon) provided with a Diaflo membrane, UM-5 (Amicon) operating under a pressure of 40 psi of nitrogen.
- Aminco concentrator Model 52 (Amicon) provided with a Diaflo membrane, UM-5 (Amicon) operating under a pressure of 40 psi of nitrogen.
- the final platinum-transferrin product is sterilized by passing through a Millex SLGS-025-0S.22 u filter (Millipore) to remove bacteria or other particulate matter which may be present, and the platinum-transferrin is stored in sterile plastic tubes (Falcon) at +5° C. until used.
- a Millex SLGS-025-0S.22 u filter Millex SLGS-025-0S.22 u filter (Millipore) to remove bacteria or other particulate matter which may be present, and the platinum-transferrin is stored in sterile plastic tubes (Falcon) at +5° C. until used.
- the transferrin which is used as a starting material can be obtained in essentially iron free form (99% pure) from Sigma Chemical Company. However, if the transferrin is not essentially iron free, it can be treated with a 0.1M phosphate buffer (KH 2 PO 4 ) adjusted with KOH to a pH of 5.0. A chelating agent such as ethylene diammine tetraacetate is then added to take free iron out of solution. An essentially iron free starting material remains. When the iron is removed from the transferrin, the red solution becomes colorless.
Abstract
Description
______________________________________ Week 1 810 mg.Week 2 257.3Week 3 184.5Week 7 724.45Week 8 939.35 Week 18 207 Week 21 317 Week 23 397 Week 24 314 Week 28 354 Week 29 340 Week 30 304 Week 35 324 TOTAL 5472.60 mg. ______________________________________
______________________________________ Patient B Week 1 1278mg Week 3 1191Week 3 1002Week 5 1196Week 7 1198Week 8 1130 Week 11 1195 Week 13 1130Week 15 1400 Week 16 1334 Week 18 1102 Week 21 1379 Week 24 841 Week 29 689 Week 32 1106 Week 35 982 Week 39 946 TOTAL 20514 ______________________________________
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US06/593,725 US4590001A (en) | 1983-03-28 | 1984-03-27 | Platinum bound to transferrin for use in the treatment of breast tumors |
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US47917383A | 1983-03-28 | 1983-03-28 | |
US06/593,725 US4590001A (en) | 1983-03-28 | 1984-03-27 | Platinum bound to transferrin for use in the treatment of breast tumors |
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US07/140,659 Reissue USRE33071E (en) | 1983-03-28 | 1988-01-04 | Platinum bound to transferrin for use in the treatment of breast tumors |
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Cited By (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4886780A (en) * | 1982-02-25 | 1989-12-12 | Faulk Ward P | Conjugates of apotransferrin proteins with anti-tumor agents |
US5122368A (en) * | 1988-02-11 | 1992-06-16 | Bristol-Myers Squibb Company | Anthracycline conjugates having a novel linker and methods for their production |
US5137877A (en) * | 1990-05-14 | 1992-08-11 | Bristol-Myers Squibb | Bifunctional linking compounds, conjugates and methods for their production |
US6328966B1 (en) * | 1994-08-11 | 2001-12-11 | I.S.I.S.P.A. | Transferrin compositions to alleviate the side effects of cytotoxic drugs |
US20020137901A1 (en) * | 2001-01-22 | 2002-09-26 | Cavanaugh Philip Gerard | Synthesis, and photodynamic therapy-mediated anti-cancer, and other uses of chlorin e6-transferrin |
US20030059375A1 (en) * | 2001-08-20 | 2003-03-27 | Transave, Inc. | Method for treating lung cancers |
US20040101553A1 (en) * | 2002-08-02 | 2004-05-27 | Transave, Inc. | Platinum aggregates and process for producing the same |
EP1424898A1 (en) * | 2001-08-20 | 2004-06-09 | Transave, Inc. | Treatment of cancers by inhalation of stable platinum-containing formulations |
US20040235712A1 (en) * | 2003-01-13 | 2004-11-25 | Lippard Stephen J. | Coordination complexes having tethered therapeutic agents and/or targeting moieties, and methods of making and using the same |
US20050249822A1 (en) * | 2004-03-18 | 2005-11-10 | Transave, Inc. | Administration of cisplatin by inhalation |
US20060034906A1 (en) * | 2004-05-21 | 2006-02-16 | Transave, Inc. | Treatment of lung diseases and pre-lung disease conditions |
US20060246124A1 (en) * | 2004-11-08 | 2006-11-02 | Pilkiewicz Frank G | Methods of treating cancer with lipid-based platinum compound formulations administered intraperitoneally |
US20070065522A1 (en) * | 2004-03-18 | 2007-03-22 | Transave, Inc. | Administration of high potency platinum compound formulations by inhalation |
US20070190182A1 (en) * | 2005-11-08 | 2007-08-16 | Pilkiewicz Frank G | Methods of treating cancer with high potency lipid-based platinum compound formulations administered intraperitoneally |
US20080187578A1 (en) * | 2002-08-02 | 2008-08-07 | Transave, Inc. | Platinum Aggregates and Process for Producing the Same |
US20090270785A1 (en) * | 2004-12-30 | 2009-10-29 | Tomas Fabo | Self-Adhesive Dressing |
US9107824B2 (en) | 2005-11-08 | 2015-08-18 | Insmed Incorporated | Methods of treating cancer with high potency lipid-based platinum compound formulations administered intraperitoneally |
US11291644B2 (en) | 2012-09-04 | 2022-04-05 | Eleison Pharmaceuticals, Llc | Preventing pulmonary recurrence of cancer with lipid-complexed cisplatin |
-
1984
- 1984-03-27 US US06/593,725 patent/US4590001A/en not_active Ceased
Non-Patent Citations (5)
Title |
---|
Aisen et al., "The Chromium, Magnesium and Cobalt Complexes of Transferrin", J. Biol. Chem., 244, No. 17, pp. 4628-4633. |
Aisen et al., The Chromium, Magnesium and Cobalt Complexes of Transferrin , J. Biol. Chem., 244, No. 17, pp. 4628 4633. * |
Bodanszky et al, Side Reactions in . . . , in The Peptides, vol. 5, Gross et al. eds, 1983, p. 156. * |
Stjernholm et al, "The Binding of Platinum to Human Transferrin", Bioinorganic Chem., 9, 277-280 (1978). |
Stjernholm et al, The Binding of Platinum to Human Transferrin , Bioinorganic Chem., 9, 277 280 (1978). * |
Cited By (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4886780A (en) * | 1982-02-25 | 1989-12-12 | Faulk Ward P | Conjugates of apotransferrin proteins with anti-tumor agents |
US5122368A (en) * | 1988-02-11 | 1992-06-16 | Bristol-Myers Squibb Company | Anthracycline conjugates having a novel linker and methods for their production |
US5137877A (en) * | 1990-05-14 | 1992-08-11 | Bristol-Myers Squibb | Bifunctional linking compounds, conjugates and methods for their production |
US5349066A (en) * | 1990-05-14 | 1994-09-20 | Bristol-Myers Squibb Company | Bifunctional linking compounds, conjugates and methods for their production |
US6328966B1 (en) * | 1994-08-11 | 2001-12-11 | I.S.I.S.P.A. | Transferrin compositions to alleviate the side effects of cytotoxic drugs |
US20020137901A1 (en) * | 2001-01-22 | 2002-09-26 | Cavanaugh Philip Gerard | Synthesis, and photodynamic therapy-mediated anti-cancer, and other uses of chlorin e6-transferrin |
US20030059375A1 (en) * | 2001-08-20 | 2003-03-27 | Transave, Inc. | Method for treating lung cancers |
EP1424898A1 (en) * | 2001-08-20 | 2004-06-09 | Transave, Inc. | Treatment of cancers by inhalation of stable platinum-containing formulations |
EP1424898A4 (en) * | 2001-08-20 | 2008-04-02 | Transave Inc | Treatment of cancers by inhalation of stable platinum-containing formulations |
US20040101553A1 (en) * | 2002-08-02 | 2004-05-27 | Transave, Inc. | Platinum aggregates and process for producing the same |
US9186322B2 (en) | 2002-08-02 | 2015-11-17 | Insmed Incorporated | Platinum aggregates and process for producing the same |
US20080187578A1 (en) * | 2002-08-02 | 2008-08-07 | Transave, Inc. | Platinum Aggregates and Process for Producing the Same |
US20040235712A1 (en) * | 2003-01-13 | 2004-11-25 | Lippard Stephen J. | Coordination complexes having tethered therapeutic agents and/or targeting moieties, and methods of making and using the same |
US7138520B2 (en) | 2003-01-13 | 2006-11-21 | Massachusetts Institute Of Technology | Coordination complexes having tethered therapeutic agents and/or targeting moieties, and methods of making and using the same |
US20050249822A1 (en) * | 2004-03-18 | 2005-11-10 | Transave, Inc. | Administration of cisplatin by inhalation |
US20070065522A1 (en) * | 2004-03-18 | 2007-03-22 | Transave, Inc. | Administration of high potency platinum compound formulations by inhalation |
US20060034906A1 (en) * | 2004-05-21 | 2006-02-16 | Transave, Inc. | Treatment of lung diseases and pre-lung disease conditions |
US20060246124A1 (en) * | 2004-11-08 | 2006-11-02 | Pilkiewicz Frank G | Methods of treating cancer with lipid-based platinum compound formulations administered intraperitoneally |
US20090270785A1 (en) * | 2004-12-30 | 2009-10-29 | Tomas Fabo | Self-Adhesive Dressing |
US7888545B2 (en) * | 2004-12-30 | 2011-02-15 | Mölnlycke Heath Care AB | Self-adhesive dressing |
US20070190182A1 (en) * | 2005-11-08 | 2007-08-16 | Pilkiewicz Frank G | Methods of treating cancer with high potency lipid-based platinum compound formulations administered intraperitoneally |
US9107824B2 (en) | 2005-11-08 | 2015-08-18 | Insmed Incorporated | Methods of treating cancer with high potency lipid-based platinum compound formulations administered intraperitoneally |
US11291644B2 (en) | 2012-09-04 | 2022-04-05 | Eleison Pharmaceuticals, Llc | Preventing pulmonary recurrence of cancer with lipid-complexed cisplatin |
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